Adherence to guidelines for oral anticoagulation after venous thrombosis and pulmonary embolism.
Guidelines for oral anticoagulation after deep venous thrombosis (DVT) or pulmonary embolism (PE) have recommended that patients be anticoagulated for at least 3 months after hospital discharge. We sought to determine whether this recommendation was being followed and what patient characteristics predict a shorter than recommended duration of therapy. Retrospective cohort study using linked health care claims data. Routine clinical practice. Five hundred seventy-three members of New Jersey's Medicaid or Pharmacy Assistance for the Aged and Disabled programs aged 65 years and older who were hospitalized for DVT or PE between January 1, 1991 and June 30, 1994. Of the 573 patients, 129 (23%) filled prescriptions covering less than 90 days of oral anticoagulant therapy. In multivariate models, African-American race was associated with an increased risk of a shorter than recommended duration of therapy (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.14 to 3.08), but age and gender were not. Patients who used anticoagulants in the year prior to admission were less likely to have a short duration of therapy (OR, 0.30; 95% CI, 0.12 to 0.78), than were patients with PE (OR, 0.58; 95% CI, 0.38 to 0.88). Nearly a quarter of those anticoagulated following DVT or PE received therapy for less than the recommended length of time after hospital discharge, with African Americans more likely to have a shorter than recommended course of treatment. Further research is needed to evaluate the causes of shorter than recommended duration of therapy and racial disparities in anticoagulant use.


Methods for assessment of patient adherence to removable orthoses used after surgery or trauma to the appendicular skeleton: a systematic review.
Patient adherence to treatment is a key determinant of outcome for healthcare interventions. Whilst non-adherence has been well evidenced in settings such as drug therapy, information regarding patient adherence to orthoses, particularly in the acute setting, is lacking. The aim of this systematic review was to identify, summarise, and critically appraise reported methods for assessing adherence to removable orthoses in adults following acute injury or surgery. Comprehensive searches of the Ovid versions of MEDLINE, Embase, AMED, CINAHL, Central, the Cochrane Database of Systematic Reviews, and SPORTDiscus identified complete papers published in English between 1990 and September 2018 reporting measurement of adherence to orthoses in adults following surgery or trauma to the appendicular skeleton. Only primary studies with reference to adherence in the title/abstract were included to maintain the focus of the review. Data extraction included study design, sample size, study population, orthosis studied, and instructions for use. Details of methods for assessing adherence were extracted, including instrument/method used, frequency of completion, number of items (if applicable), and score (if any) used to evaluate adherence overall. Validity and reliability of identified methods were assessed together with any conclusions drawn between adherence and outcomes in the study. Seventeen papers (5 randomised trials, 10 cohort studies, and 2 case series) were included covering upper (n = 13) and lower (n = 4) limb conditions. A variety of methods for assessing adherence were identified, including questionnaires (n = 10) with single (n = 3) or multiple items (n = 7), home diaries (n = 4), and discussions with the patient (n = 3). There was no consistency in the target behaviour assessed or in the timing or frequency of assessment or the scoring systems used. None of the measures was validated for use in the target population. Measurement and reporting of adherence to orthosis use is currently inconsistent. Further research is required to develop a measurement tool that provides a rigorous and reproducible assessment of adherence in this acute population. PROSPERO: CRD42016048462. Registered on 17/10/2016.


Hemodynamics in transgenic mice with overexpression of atrial natriuretic factor.
The circulatory effects associated with lifelong plasma atrial natriuretic factor (ANF) elevation were examined by generating transgenic mice, which constitutively express a fusion gene consisting of the transthyretin promoter and the ANF structural gene. These mice have chronically elevated ANF levels as compared with their nontransgenic siblings. Transgenic animals exhibited immunoreactive ANF levels that were nearly fivefold higher than those measured in nontransgenic littermates. Systemic and regional hemodynamics and blood volumes were explored by using modifications of the reference microsphere and dilution techniques. Mean arterial pressure was reduced by 24 mm Hg, associated with a 27% reduction in total heart weight. This chronic reduction in blood pressure was due to a 21% reduction in total peripheral resistance, whereas cardiac output, stroke volume, and heart rate were not significantly altered, despite a 15% elevation in plasma volume. Transgenic mice displayed reductions of 35%, 33%, 32%, and 19% in muscle, skin, brain, and renal vascular resistance, respectively, whereas coronary and splanchnic resistances were not significantly altered. The findings complement earlier data from chronically infused normotensive mammals and suggest that these mice are an excellent model for investigating the effects of lifelong ANF elevation.


Daily Melatonin Administration Attenuates Age-Dependent Disturbances of Cardiovascular Rhythms.
Increased blood pressure and reduced robustness of circadian rhythms are frequently reported in elderly subjects. The present study was aimed to investigate whether such changes can be reversed by daily melatonin ingestion. 97 normotensive and hypertensive volunteers of both genders and 63 to 91 years old participated. They lived in the Tyumen Elderly Veteran House on a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted for three weeks. After one control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen(TM)) each day at 22:30 h for two weeks. The other 34 subjects were placebo-treated. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured using semi-automated devices at 03:00, 08:00, 11:00, 14:00, 17:00, 23:00 h each day of the first and the third week. Specially trained personnel made the measurements, taking care not to disturb subjects' sleep. Rhythm characteristics were estimated by means of single and population-mean cosinor analyses. Bingham test was used to compare rhythm parameters between groups and investigated physiologic variables. The 24-h HR rhythm was monophasic as described in other studies for young subjects though with a steeper increase in the morning. The daily SBP and DBP rhythms were bimodal. In reference to previously reported data of younger subjects, mean blood pressure of our cohort was elevated, particularly the nocturnal fall was less pronounced. Also, the overall SBP variability was higher as was the percentage of the 12-h component. Both values and also the SBP and DBP levels were reduced during melatonin treatment. The hypotensive effect of melatonin was most pronounced between 3:00 and 8:00 in the morning, i.e. at the time of the highest risk of adverse cardiovascular events, and in subjects with highest BP values before treatment. Moreover, the morning increase of HR was gentler what could have been of additional benefit. Melatonin has a direct hypotensive effect. Also, it stabilizes the internal temporal order enhancing the circadian component and the synchronization between rhythms of different physiological functions. This may further improve health and welfare of elderly subjects and particularly of those with hypertension. Taken together our data show the usefulness of melatonin for adjuvant medication.


Cerebral vasculitis of medium-sized vessels as a possible mechanism of brain damage in COVID-19 patients.
Cerebral complications related to COVID-19 were recently reported, and the underlying mechanisms of brain damage remain uncertain, probably multifactorial. Among various hypotheses suggested, a possible vasculitis was issued but never confirmed. Herein, we aimed to describe brain MRIs focused on the intracranial vessel wall in a population of COVID-19 patients with neurologic manifestations. Between March 1 and May 31, 2020, 69 consecutive COVID-19 patients with neurologic manifestations underwent a brain MRI allowing the study of the intracranial vessel wall at Strasbourg University hospitals and were retrospectively included. During the same period, 25 consecutive patients, without suspicion of SARS-CoV-2 infection, underwent a brain MRI urgently, with the same imaging protocols. A vasculitis seemed likely when imaging demonstrated vessel wall thickening with homogeneous and concentric enhancement. Among the 69 COVID-19 patients included, 11 (16%) presented arterial vessel wall thickening with homogeneous and concentric enhancement, compatible with cerebral vasculitis. These neuroimaging findings were not found among the 25 patients without SARS-CoV-2 infection, and the difference was statistically significant (p = 0.03). Middle cerebral arteries, basilar artery, and posterior cerebral arteries were the most frequent vessels involved. For nine of them, imaging demonstrated ischemic or hemorrhagic complications. Cerebral vasculitis of medium-sized vessels seems to be one of the mechanisms at the origin of brain damage related to COVID-19.


Assessment of Dengue virus helicase and methyltransferase as targets for fragment-based drug discovery.
Seasonal and pandemic flaviviruses continue to be leading global health concerns. With the view to help drug discovery against Dengue virus (DENV), a fragment-based experimental approach was applied to identify small molecule ligands targeting two main components of the flavivirus replication complex: the NS3 helicase (Hel) and the NS5 mRNA methyltransferase (MTase) domains. A library of 500 drug-like fragments was first screened by thermal-shift assay (TSA) leading to the identification of 36 and 32 fragment hits binding Hel and MTase from DENV, respectively. In a second stage, we set up a fragment-based X-ray crystallographic screening (FBS-X) in order to provide both validated fragment hits and structural binding information. No fragment hit was confirmed for DENV Hel. In contrast, a total of seven fragments were identified as DENV MTase binders and structures of MTase-fragment hit complexes were solved at resolution at least 2.0Å or better. All fragment hits identified contain either a five- or six-membered aromatic ring or both, and three novel binding sites were located on the MTase. To further characterize the fragment hits identified by TSA and FBS-X, we performed enzymatic assays to assess their inhibition effect on the N7- and 2'-O-MTase enzymatic activities: five of these fragment hits inhibit at least one of the two activities with IC50 ranging from 180μM to 9mM. This work validates the FBS-X strategy for identifying new anti-flaviviral hits targeting MTase, while Hel might not be an amenable target for fragment-based drug discovery (FBDD). This approach proved to be a fast and efficient screening method for FBDD target validation and discovery of starting hits for the development of higher affinity molecules that bind to novel allosteric sites.


Mechanisms for the prevention of marine bioinvasions for better biosecurity.
Biosecurity management allows countries to meet a number of international obligations and provides some protection from potential degradation of environmental, economic, social and cultural values. Ocean governance relies on the precepts of ecologically sustainable development to manage the multiple uses in the coastal zone. The increasing reliance on aquaculture to provide food security and economic development has led to an increase in the use of non-native target species grown as food sources. Increased economic activity has led to shifting trade patterns and increased efficiencies in vessels with the resulting increase in the number of introduced marine species via ballast water and hull fouling. Herein we review the different marine biosecurity strategies and legislation that have been implemented internationally and locally that aid in preventing and managing introduced marine species, with some attention to Australia and New Zealand as examples. Typical tools being used include quarantine, Import Health Standards, voluntary cleaning guidelines, and risk assessment, all of which aim to prevent introductions.


Training locomotor networks.
For a complete adult spinal rat to regain some weight-bearing stepping capability, it appears that a sequence of specific proprioceptive inputs that are similar, but not identical, from step to step must be generated over repetitive step cycles. Furthermore, these cycles must include the activation of specific neural circuits that are intrinsic to the lumbosacral spinal cord segments. For these sensorimotor pathways to be effective in generating stepping, the spinal circuitry must be modulated to an appropriate excitability level. This level of modulation is sustained from supraspinal input in intact, but not spinal, rats. In a series of experiments with complete spinal rats, we have shown that an appropriate level of excitability of the spinal circuitry can be achieved using widely different means. For example, this modulation level can be acquired pharmacologically, via epidural electrical stimulation over specific lumbosacral spinal cord segments, and/or by use-dependent mechanisms such as step or stand training. Evidence as to how each of these treatments can "tune" the spinal circuitry to a "physiological state" that enables it to respond appropriately to proprioceptive input will be presented. We have found that each of these interventions can enable the proprioceptive input to actually control extensive details that define the dynamics of stepping over a range of speeds, loads, and directions. A series of experiments will be described that illustrate sensory control of stepping and standing after a spinal cord injury and the necessity for the "physiological state" of the spinal circuitry to be modulated within a critical window of excitability for this control to be manifested. The present findings have important consequences not only for our understanding of how the motor pattern for stepping is formed, but also for the design of rehabilitation intervention to restore lumbosacral circuit function in humans following a spinal cord injury.


Mapping the visual brain: how and why.
Over the past 15 years, techniques for identifying visual areas using magnetic resonance imaging (MRI) in human subjects have been applied widely to multiple populations. This review will cover the basic techniques of using functional MRI and very high-resolution structural MRI to determine boundaries between different areas of the visual cortex. Recent applications of these methods to ophthalmological patient populations are discussed, and the future potential applications of very high field strength MRI are considered.


OsHKT1;4-mediated Na(+) transport in stems contributes to Na(+) exclusion from leaf blades of rice at the reproductive growth stage upon salt stress.
Na(+) exclusion from leaf blades is one of the key mechanisms for glycophytes to cope with salinity stress. Certain class I transporters of the high-affinity K(+) transporter (HKT) family have been demonstrated to mediate leaf blade-Na(+) exclusion upon salinity stress via Na(+)-selective transport. Multiple HKT1 transporters are known to function in rice (Oryza sativa). However, the ion transport function of OsHKT1;4 and its contribution to the Na(+) exclusion mechanism in rice remain to be elucidated. Here, we report results of the functional characterization of the OsHKT1;4 transporter in rice. OsHKT1;4 mediated robust Na(+) transport in Saccharomyces cerevisiae and Xenopus laevis oocytes. Electrophysiological experiments demonstrated that OsHKT1;4 shows strong Na(+) selectivity among cations tested, including Li(+), Na(+), K(+), Rb(+), Cs(+), and NH4 (+), in oocytes. A chimeric protein, EGFP-OsHKT1;4, was found to be functional in oocytes and targeted to the plasma membrane of rice protoplasts. The level of OsHKT1;4 transcripts was prominent in leaf sheaths throughout the growth stages. Unexpectedly however, we demonstrate here accumulation of OsHKT1;4 transcripts in the stem including internode II and peduncle in the reproductive growth stage. Moreover, phenotypic analysis of OsHKT1;4 RNAi plants in the vegetative growth stage revealed no profound influence on the growth and ion accumulation in comparison with WT plants upon salinity stress. However, imposition of salinity stress on the RNAi plants in the reproductive growth stage caused significant Na(+) overaccumulation in aerial organs, in particular, leaf blades and sheaths. In addition, (22)Na(+) tracer experiments using peduncles of RNAi and WT plants suggested xylem Na(+) unloading by OsHKT1;4. Taken together, our results indicate a newly recognized function of OsHKT1;4 in Na(+) exclusion in stems together with leaf sheaths, thus excluding Na(+) from leaf blades of a japonica rice cultivar in the reproductive growth stage, but the contribution is low when the plants are in the vegetative growth stage.


Colonic pericrypt sheath cells: characterisation of cell type with new monoclonal antibody.
A new monoclonal antibody, PR 2D3, was raised against a crude homogenate of normal colorectal mucosa and found to react with the cells in the pericrypt sheath. It also reacted with smooth muscle throughout the body and, in specific sites, with those mesenchymal cells known as myofibroblasts. It did not react with cardiac or skeletal muscle, nor with fibroblasts. PR 2D3 is an IgG1 antibody and identifies a membrane component of about 140 K molecular weight. The pericrypt cells have been described as fibroblasts, but in view of the specificity of PR 2D3 for smooth muscle, and its selective staining of the colonic pericrypt cells, this cell type was re-examined for other smooth muscle properties. Ultrastructurally, the cells had many characteristics in common with smooth muscle and were identical with the myofibroblasts of the umbilical cord. On immunocytochemical examination they were found to contain desmin, myosin, and filamin. The confirmation that the pericrypt cells are myofibroblasts suggest that they have both contractile and secretory roles.


Autoimmune disease incidence among women prenatally exposed to diethylstilbestrol.
Animal studies have suggested that prenatal diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women. A group of women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON), and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were and who were not prenatally DES-exposed. Overall, there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (RR 1.2; 95% CI 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR 4.9; 95% CI 1.1, 21.6) and an inverse association among women who were 45 years and older (RR 0.1; 95% CI 0.01, 0.7). Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study.


Comparative genomic analysis of Klebsiella pneumoniae subsp. pneumoniae KP617 and PittNDM01, NUHL24835, and ATCC BAA-2146 reveals unique evolutionary history of this strain.
Klebsiella pneumoniae subsp. pneumoniae KP617 is a pathogenic strain that coproduces OXA-232 and NDM-1 carbapenemases. We sequenced the genome of KP617, which was isolated from the wound of a Korean burn patient, and performed a comparative genomic analysis with three additional strains: PittNDM01, NUHL24835 and ATCC BAA-2146. The complete genome of KP617 was obtained via multi-platform whole-genome sequencing. Phylogenetic analysis along with whole genome and multi-locus sequence typing of genes of the Klebsiella pneumoniae species showed that KP617 belongs to the WGLW2 group, which includes PittNDM01 and NUHL24835. Comparison of annotated genes showed that KP617 shares 98.3 % of its genes with PittNDM01. Nineteen antibiotic resistance genes were identified in the KP617 genome: bla OXA-1 and bla SHV-28 in the chromosome, bla NDM-1 in plasmid 1, and bla OXA-232 in plasmid 2 conferred resistance to beta-lactams; however, colistin- and tetracycline-resistance genes were not found. We identified 117 virulence factors in the KP617 genome, and discovered that the genes encoding these factors were also harbored by the reference strains; eight genes were lipopolysaccharide-related and four were capsular polysaccharide-related. A comparative analysis of phage-associated regions indicated that two phage regions are specific to the KP617 genome and that prophages did not act as a vehicle for transfer of antimicrobial resistance genes in this strain. Whole-genome sequencing and bioinformatics analysis revealed similarity in the genome sequences and content, and differences in phage-related genes, plasmids and antimicrobial resistance genes between KP617 and the references. In order to elucidate the precise role of these factors in the pathogenicity of KP617, further studies are required.


A chronological model for the Late Paleolithic at Shuidonggou Locality 2, North China.
The site of Shuidonggou Locality 2 offers important evidence for the Late Paleolithic sequence of north China. The site not only contains one of the earliest instances of ornamental freshwater shell and ostrich eggshell beads in the region, but also stone artifacts with features arguably resembling the Initial Upper Paleolithic (IUP) blade technology found farther north. The appearance of these innovative archaeological forms have been attributed to the arrival of hominin populations, possibly modern humans, into the region during Marine Isotope Stage 3. Yet, the chronology of the site remains debated due to ambiguities in the existing dates. In this study, we conduct a systematical radiocarbon analysis of charcoal and ostrich eggshell samples obtained throughout the site sequence. Both acid-base-acid and the more stringent acid-base-oxidation pretreatment methods were applied to the charcoal samples. The resulting ages follow an age-depth relationship that is consistent with the stratigraphic profile. In line with previous stratigraphic assessments, Bayesian age modeling suggests that site formation history can be split into two phases: an early phase 43-35 cal kBP associated with a lacustrine depositional environment, and a later phase 35-28 cal kBP associated with rapid terrestrial silt accumulation. The chronology of the archaeological layers containing IUP-like artifacts are placed at 43-39 cal kBP and 35-34 cal kBP respectively. This finding supports the interpretation that an IUP-like blade technology appeared in the SDG region by at least ~41 ka.


Lentinan administration relieves gut barrier dysfunction induced by rotavirus in a weaned piglet model.
Rotavirus (RV) is a pathogen that induces severe diarrhea in infants and young animals. Shiitake mushroom is a traditional food, which can improve physiological function, including gut health. Lentinan (LNT) is the main functional component of Shiitake mushroom. This study aimed to verify whether LNT administration could improve intestinal barrier function, thereby decreasing RV-induced diarrhea in a porcine model. According to initial weight and origin, a total of 28 weaned piglets were randomly fed 2 diets containing 0 or 84 mg kg-1 LNT for 19 d (n = 14). On day 15, RV was orally infused to half of the pigs in each group. RV-induced diarrhea (P < 0.05), the positive rate of RV non-structural protein 4 (NSP4), impaired intestinal morphology, antioxidant capacity and microbiota (P < 0.05), and increased apoptosis of jejunal epithelial cells (P < 0.05) were assessed in the piglets. Dietary LNT supplementation was found to improve intestinal morphology, permeability, antioxidant capacity and microbiota (P < 0.05). Supplementation also further alleviated the effects of RV infection on diarrhea, intestinal morphology, permeability, antioxidant capacity, microbiota and apoptosis of jejunal epithelial cells in piglets (P < 0.05). Thus, these results suggest that LNT administration relieved RV-induced diarrhea in piglets, which could be due to the increase in antioxidant capacity, reduction in apoptosis and improvement of the microbiota-increased gut barrier.


Deposition and transport of Pseudomonas aeruginosa in porous media: lab-scale experiments and model analysis.
In this study, the deposition and transport of Pseudomonas aeruginosa on sandy porous materials have been investigated under static and dynamic flow conditions. For the static experiments, both equilibrium and kinetic batch tests were performed at a 1:3 and 3:1 soil:solution ratio. The batch data were analysed to quantify the deposition parameters under static conditions. Column tests were performed for dynamic flow experiments with KCl solution and bacteria suspended in (1) deionized water, (2) mineral salt medium (MSM) and (3) surfactant + MSM. The equilibrium distribution coefficient (K(d)) was larger at a 1:3 (2.43 mL g(-1)) than that at a 3:1 (0.28 mL g(-1)) soil:solution ratio. Kinetic batch experiments showed that the reversible deposition rate coefficient (k(att)) and the release rate coefficient (k(det)) at a soil:solution ratio of 3:1 were larger than those at a 1:3 ratio. Column experiments showed that an increase in ionic strength resulted in a decrease in peak concentration of bacteria, mass recovery and tailing of the bacterial breakthrough curve (BTC) and that the presence of surfactant enhanced the movement of bacteria through quartz sand, giving increased mass recovery and tailing. Deposition parameters under dynamic condition were determined by fitting BTCs to four different transport models, (1) kinetic reversible, (2) two-site, (3) kinetic irreversible and (4) kinetic reversible and irreversible models. Among these models, Model 4 was more suitable than the others since it includes the irreversible sorption term directly related to the mass loss of bacteria observed in the column experiment. Applicability of the parameters obtained from the batch experiments to simulate the column breakthrough data is evaluated.


Aromatic amino acid transaminase in rat intestine.
The transamination of aromatic l-amino acids (5-hydroxytryptophan, tryptophan, tyrosine, phenylalanine and kynurenine) was shown to be catalysed by enzyme preparations from rat small intestine. On the basis of the partial purification and characterization of these aromatic amino acid transaminases, it is suggested that rat small intestine contains several kinds of aromatic amino acid transaminases.


Estimating the potential impacts of large mesopredators on benthic resources: integrative assessment of spotted eagle ray foraging ecology in Bermuda.
Declines of large sharks and subsequent release of elasmobranch mesopredators (smaller sharks and rays) may pose problems for marine fisheries management as some mesopredators consume exploitable shellfish species. The spotted eagle ray (Aetobatus narinari) is the most abundant inshore elasmobranch in subtropical Bermuda, but its predatory role remains unexamined despite suspected abundance increases and its hypothesized specialization for mollusks. We utilized a combination of acoustic telemetry, benthic invertebrate sampling, gut content analysis and manipulative experiments to assess the impact of spotted eagle rays on Bermudian shellfish resources. Residency and distribution of adult spotted eagle rays was monitored over two consecutive summers in Harrington Sound (HS), an enclosed inshore lagoon that has historically supported multiple recreational and commercial shellfish species. Telemetered rays exhibited variable fidelity (depending on sex) to HS, though generally selected regions that supported relatively high densities of potential mollusk prey. Gut content analysis from rays collected in HS revealed a diet of mainly bivalves and a few gastropods, with calico clam (Macrocallista maculata) representing the most important prey item. Manipulative field and mesocosm experiments with calico clams suggested that rays selected prey patches based on density, though there was no evidence of rays depleting clam patches to extirpation. Overall, spotted eagle rays had modest impacts on local shellfish populations at current population levels, suggesting a reduced role in transmitting cascading effects from apex predator loss. However, due to the strong degree of coupling between rays and multiple protected mollusks in HS, ecosystem-based management that accounts for ray predation should be adopted.


Anatomical Assessment of the Endoscopic Assisted Lateral Supraorbital Approach and Endoscopic Endonasal Transclival Approach to Basilar Apex Aneurysms.
To assess the feasibility of using an endoscopic-assisted lateral supraorbital (LSO) approach and an endoscopic endonasal transclival approach (EETA) for basilar apex (BAX) aneurysms. Ten cases with LSO approaches, with or without posterior clinoidectomy and endoscopic assistance, and 10 cases with EETA, with or without drilling of the dorsum sellae, were performed on 20 cadaveric heads. Anatomical exposure and surgical freedom at the BAX were evaluated. Anatomical exposure provided by the LSO approach was limited to the BAX and ipsilateral posterior cerebral artery (PCA) and increased with a mean value of 5.0 mm after posterior clinoidectomy; the basilar artery, contralateral PCA, and superior cerebellar arteries (SCAs) were visualized in all cases. Accordingly, surgical freedom was larger. Endoscopic assistance provided a significant increase in basilar artery exposure; however, surgical freedom did not increase markedly. The main advantage of EETA was the greatest exposure of the basilar artery. With drilling of the dorsum sellae, anatomical exposure increased by a mean value of 3.4 mm, and provided the greatest amount of surgical freedom and visualization of the basilar artery terminal bifurcation and of the SCAs in all cases. The endoscopic-assisted LSO approach and the EETA may represent a feasible approach for treatment of BAX aneurysms lying within 5.0 mm below and within 3.4 mm above the dorsum sellae.


Use of three-dimensional computed tomography for diagnosis and treatment planning for open-mouth jaw locking in a cat.
A 2.5-year-old spayed female Persian cat was evaluated for acute inability to close its mouth. A wry-mouth malocclusion was evident, and the right side of the mandible was longer than the left side. The right mandibular tooth row appeared to be lowered. The lower jaw was persistently maintained in an open position. The presumptive diagnosis was open-mouth jaw locking. Diagnostic imaging with computed tomography and 3-dimensional reconstruction was performed for definitive diagnosis and to achieve a better understanding of the lesions. Imaging revealed locking of the right ramus of the mandible, which was displaced ventrolaterally, causing the coronoid process to impinge on the right zygomatic arch. A bilateral partial ostectomy of the rostroventral margins of the zygomatic arches with an autogenous fat graft implantation was performed. The cat recovered without complications and by the following morning was bright, alert, and responsive and eating canned cat food comfortably. One year after surgery, the owner reported that the cat had continued to function well, was eating normally, and had not had any observed locking episodes since surgery. Unlike radiographic imaging, computed tomography may be used to create 3-dimensional reconstructions of structures in cases of suspected open-mouth jaw locking; improve evaluation of the lesions; and improve decision-making and client education for diagnosis, treatment options, and prognosis.


Geographic variation in colorectal cancer survival and the role of small-area socioeconomic deprivation: a multilevel survival analysis of the NIH-AARP Diet and Health Study Cohort.
Adverse socioeconomic conditions, at both the individual and the neighborhood level, increase the risk of colorectal cancer (CRC) death, but little is known regarding whether CRC survival varies geographically and the extent to which area-level socioeconomic deprivation affects this geographic variation. Using data from the National Institutes of Health (NIH)-AARP Diet and Health Study, the authors examined geographic variation and the role of area-level socioeconomic deprivation in CRC survival. CRC cases (n = 7,024), identified during 1995-2003, were followed for their CRC-specific vital status through 2005 and overall vital status through 2006. Bayesian multilevel survival models showed that there was significant geographic variation in overall (variance = 0.2, 95% confidence interval (CI): 0.1, 0.2) and CRC-specific (variance = 0.3, 95% CI: 0.1, 0.4) risk of death. More socioeconomically deprived neighborhoods had a higher overall risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.4) and a higher CRC-specific risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.5). However, neighborhood socioeconomic deprivation did not account for the geographic variation in overall and CRC-specific risks of death. In future studies, investigators should evaluate other neighborhood characteristics to help explain geographic heterogeneity in CRC survival. Such research could facilitate interventions for reducing geographic disparity in CRC survival.


Angiotensin-converting enzyme inhibition attenuates arterial constrictor responses in experimental hypertension.
Angiotensin-converting enzyme inhibition has been shown to attenuate arterial contractions, but the underlying mechanisms have not been clarified in detail. Therefore, we investigated the effects of 10-week-long quinapril therapy (10 mg kg-1 day-1) on responses of mesenteric arterial rings in vitro in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats. The hypertrophy of cardiac muscle and mesenteric arterial smooth muscle was effectively reduced in SHR by quinapril treatment. Maximal contractile force generation to 5-hydroxy-tryptamine was reduced in endothelium-intact and -denuded rings of quinapril-treated SHR when compared with untreated SHR. Contractile sensitivity of endothelium-intact rings to 5-hydroxytryptamine was also attenuated in SHR by quinapril, whereas no differences were found between the study groups in sensitivity of endothelium-denuded rings. Inhibition of NO synthesis by NG-nitro-L-arginine methyl ester increased the sensitivity and contractile force generation of endothelium-intact rings to 5-hydroxytryptamine more effectively in quinapril-treated than in untreated SHR, whereas indomethacin had only minor effects on the responses in the study groups. Maximal responses and sensitivity to norepinephrine were also reduced in SHR by quinapril and were more effectively increased by NG-nitro-L-arginine in quinapril-treated than in untreated SHR. In addition, KCI-induced maximal contractions of endothelium-denuded rings were attenuated in quinapril-treated SHR. However, when the release of norepinephrine from vascular adrenergic nerve endings was eliminated by sympathectomy, no differences were found in maximal KCI-induced contractions between the study groups; this suggests that diminished contractions to KCI in quinapril-treated SHR resulted from reduced release of endogenous norepinephrine from vascular nerve endings during depolarization. The inhibitory effects of the calcium channel blocker nifedipine on arterial contractions in the Wistar-Kyoto rat groups and the quinapril-treated SHR were similar and were lower than in untreated SHR. In conclusion, the present findings suggest that effective reversal of cardiovascular hypertrophy, normalization of the function of voltage-dependent calcium channels, sympathoinhibitory action and enhanced endothelium-derived NO release can explain the attenuated arterial constrictor responses that occur after the long-term inhibition of angiotensin-converting enzyme.


Time to wake-up: sleep problems and daytime sleepiness in long-term stroke survivors.
In work with chronic stroke patients the authors observed that patients frequently appear sleepy and often comment on their poor sleep. Sleep difficulties are frequently reported and indeed clinically recognized in the acute phase post-stroke, but little is known about the sleep and daytime sleepiness of chronic stroke patients with sustained disabilities. The latter, however, deserves clarification because sleep is a critical modulator of health, daytime performance and wellbeing. The present study therefore explored the sleep and sleepiness in a chronic stroke population with sustained physical deficits. An opportunity sample of 20 patients with chronic low-functioning hemiplegia (>12 months) completed the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Medical Outcome Study Short Form 36 and Hospital Anxiety and Depression Scale. Compared to a normative healthy population, long-term stroke survivors reported poorer sleep and greater daytime sleepiness. Increased levels of sleepiness were associated with longer chronicity, whereas nocturnal sleep parameters were not. In line with clinical observations, stroke survivors with sustained physical disabilities report poorer sleep and experience greater levels of sleepiness. Further research in a larger cohort and including objective sleep measures is necessary to investigate the nature and scale of sleep difficulties and daytime sleepiness in more detail so that care and treatment strategies can be developed in due course.


Perioperative tobacco use treatments: putting them into practice.
Treatment for tobacco use is efficacious and beneficial to health. Although guidelines recommend that all patients who use tobacco are offered treatment as a part of their clinical care, implementing treatment has proven challenging. In the case of surgical patients, this lack of treatment is particularly unfortunate, as the benefits of abstinence from tobacco are immediate in terms of reducing the risk of surgical complications, including cardiovascular, respiratory, and wound related complications. Surgery also presents an opportunity for patients to quit for good and reduce the long term health risk. This review examines the principles of tobacco use treatment, the rationale for tobacco use treatment in the perioperative period, and how treatment can be incorporated into the routine care of surgical patients. The discipline of implementation science helps to frame these efforts by seeking to better understand how changes in clinical practice occur, and it has the potential to guide an evidence based approach to embedding tobacco treatment into the routine clinical care of surgical patients. This review uses the consolidated framework for implementation research, which includes five major domains, as a representative conceptual framework. A basic understanding of factors potentially important to successful implementation can help to guide clinicians who accept the challenge of implementing tobacco use treatment in surgical care.


Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine.
Concentration of urine in mammals is regulated by the antidiuretic hormone vasopressin. Binding of vasopressin to its V2 receptor leads to the insertion of water channels in apical membranes of principal cells in collecting ducts. In nephrogenic diabetes insipidus (NDI), the kidney fails to concentrate urine in response to vasopressin. A male patient with an autosomal recessive form of NDI was found to be a compound heterozygote for two mutations in the gene encoding aquaporin-2, a water channel. Functional expression studies in Xenopus oocytes revealed that each mutation resulted in nonfunctional water channel proteins. Thus, aquaporin-2 is essential for vasopressin-dependent concentration of urine.


Innovative high-surface-area CuO pretreated cotton effective in bacterial inactivation under visible light.
This study presents the first report on enhanced bacterial inactivation of E. coli by RF-plasma pretreated cotton with high-surface-area CuO powders compared with nonpretreated cotton textiles. The high-surface-area CuO (65 m/g) powder was fully characterized. The E. coli inactivation proceeded in the dark and was accelerated under visible and sunlight irradiation even at very low levels of visible light irradiation. The effect the RF-plasma pretreatment of the cotton on the binding of CuO, applied light dose, the amount of CuO loading and initial E. coli concentration on the inactivation kinetics of E. coli is reported in detail.


Metalloprotease OMA1 Fine-tunes Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability.
Mitochondria are involved in key cellular functions including energy production, metabolic homeostasis, and apoptosis. Normal mitochondrial function is preserved by several interrelated mechanisms. One mechanism - intramitochondrial quality control (IMQC) - is represented by conserved proteases distributed across mitochondrial compartments. Many aspects and physiological roles of IMQC components remain unclear. Here, we show that the IMQC protease Oma1 is required for the stability of the respiratory supercomplexes and thus balanced and tunable bioenergetic function. Loss of Oma1 activity leads to a specific destabilization of respiratory supercomplexes and consequently to unbalanced respiration and progressive respiratory decline in yeast. Similarly, experiments in cultured Oma1-deficient mouse embryonic fibroblasts link together impeded supercomplex stability and inability to maintain proper respiration under conditions that require maximal bioenergetic output. Finally, transient knockdown of OMA1 in zebrafish leads to impeded bioenergetics and morphological defects of the heart and eyes. Together, our biochemical and genetic studies in yeast, zebrafish and mammalian cells identify a novel and conserved physiological role for Oma1 protease in fine-tuning of respiratory function. We suggest that this unexpected physiological role is important for cellular bioenergetic plasticity and may contribute to Oma1-associated disease phenotypes in humans.


Health care resource utilization and costs during episodes of care for type 2 diabetes mellitus-related comorbidities.
To obtain costs of episodes of care for type 2 diabetes mellitus (T2DM)-related comorbidities. Data from the MarketScan Commercial Claims and Encounters Database were analyzed with the Medical Episode Grouper software, which uses proprietary algorithms to identify episodes of care. Episodes relevant to the T2DM population were examined, including: coronary artery disease with acute myocardial infarction, ventricular fibrillation, shock, and/or cardiac arrest (CAD episodes); cerebrovascular disease with stroke (CVD episodes); hypoglycemia; T2DM with complications (complication episodes); and renal failure. 45,350 CAD; 85,287 CVD; 29,886 hypoglycemia; 40,339 complication; and 211,673 renal failure episodes were identified. Mean (SD) episode durations were 15.2 (39.1), 25.5 (55.0), 5.9 (24.0), 21.2 (54.6), and 364.0 (0.0) days, respectively. Inpatient visits were the largest component of unadjusted costs for CAD, CVD, and complication episodes (93.4%, 78.3%, and 91.9%, respectively). Other ancillary care represented the largest component of unadjusted costs for hypoglycemia (53.3%) and renal failure (80.5%) episodes. Mean adjusted total costs were $16,435; $4558; $445; $5675; and $8765 for CAD, CVD, hypoglycemia, complication, and renal failure episodes, respectively. This study adds important information to the literature regarding costs of episodes of care for patients with T2DM in the US.


BRAF mutation is not predictive of long-term outcome in papillary thyroid carcinoma.
The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1-2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1-2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1-2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan-Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy.


Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne.
Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients.


Copper-inducible transcriptional regulation at two promoters in the Escherichia coli copper resistance determinant pco.
The pco determinant of Escherichia coli plasmid pRI1004 encodes inducible resistance to the trace element copper. The identification of two copper-dependent transcriptional initiation regions within pco that each contain a similar upstream hyphenated dyad motif is described. Deletion constructs showed that this 'copper box' motif was essential for copper-inducible activity at both pco promoters, PpcoA and PpcoE. The placement of the motif differs in the two promoters, and PpcoA contains an extended -10 nonamer typical of promoters for which RNA polymerase does not bind specifically to -35 sequences. PpcoE does not contain this motif and is the more strongly expressed promoter. The transcript from PpcoA contains the pcoABCDRS genes, while PpcoE expresses only pcoE. The induction profiles for PpcoA- and PpcoE-IacZ fusions were flattened sigmoidal curves with a gradual response to increasing copper concentration. On high-copy-number plasmids, zinc was found also to induce transcription from both promoters in vivo. Both promoters showed inducible activity in the absence of pcoRS, the plasmid-borne two-component regulatory system, indicating that a second trans-acting regulatory system is present on the chromosome. The pcoR product showed repressor action in the absence of pcoS, while still allowing induction, suggesting the chromosome encoded a similar two-component system to pco. TnphoA insertion mutagenesis identified chromosomal genes which affected promoter expression, including ptsH, ptsI (sugar phosphotransferase system) and cya (adenylate cyclase). The results support that idea that pco-encoded copper resistance is an auxiliary mechanism for handling copper, the regulation of which is integrated with the chromosomal regulation of cellular copper metabolism.


Use of cardiac sphericity index and manubrium heart scores to assess radiographic cardiac silhouettes in large-and small-breed dogs with and without cardiac disease.
To evaluate the usefulness of manubrium heart scores (MHSs) in distinguishing between dogs with and without cardiac disease. 184 client-owned dogs with (n = 64) and without (120) cardiac disease. Medical records, including thoracic radiographic images, of dogs that either had echocardiographically confirmed moderate to severe cardiac disease with cardiomegaly (case dogs) or were healthy and without evidence of cardiac disease (control dogs) were retrospectively reviewed. From right lateral thoracic radiographic images, the lengths of the cardiac short and long axes and the manubrium were measured and cardiac sphericity indices (CSIs), MHSs, and vertebral heart scores were determined. Dogs were grouped on the basis of whether they did or did not have cardiac disease (case dogs vs control dogs), breed size (large-breed dogs vs small-breed dogs), and whether cardiac disease affected the right side of the heart (right-sided cardiac disease) or the left side of heart (left-sided cardiac disease). Results were compared across groups. The mean CSI was greatest in case dogs with right-sided cardiac disease, compared with other groups. In dogs of the present study, a combination of high short-, long-, and overall-MHSs was more suggestive of left-sided cardiac disease, whereas a high short-MHS without high long- and overall-MHSs was more suggestive of right-sided cardiac disease. Results indicated that MHSs could be useful, objective values to help assess dogs for potential heart disease, and we recommend that MHSs be added to the diagnostic tools used by veterinarians when screening for heart disease in dogs.


Quantitative description of fluid flows produced by left-right cilia in zebrafish.
Motile cilia generate directional flows that move mucus through airways, cerebrospinal fluid through brain ventricles, and oocytes through fallopian tubes. In addition, specialized monocilia beat in a rotational pattern to create asymmetric flows that are involved in establishing the left-right (LR) body axis during embryogenesis. These monocilia, which we refer to as "left-right cilia," produce a leftward flow of extraembryonic fluid in a transient "organ of asymmetry" that directs asymmetric signaling and development of LR asymmetries in the cardiovascular system and gastrointestinal tract. The asymmetric flows are thought to establish a chemical gradient and/or activate mechanosensitive cilia to initiate calcium ion signals and a conserved Nodal (TGFβ) pathway on the left side of the embryo, but the mechanisms underlying this process remain unclear. The zebrafish organ of asymmetry, called Kupffer's vesicle, provides a useful model system for investigating LR cilia and cilia-powered fluid flows. Here, we describe methods to visualize flows in Kupffer's vesicle using fluorescent microspheres and introduce a new and freely available MATLAB particle tracking code to quantitatively describe these flows. Analysis of normal and aberrant flows indicates this approach is useful for characterizing flow properties that impact LR asymmetry and may be more broadly applicable for quantifying other cilia flows.


MR imaging for acute nontraumatic abdominopelvic pain: rationale and practical considerations.
Medical imaging is becoming an increasingly vital component of patient care in the emergency department. Computed tomography has been the diagnostic imaging method of choice for emergency department patients with acute abdominopelvic pain; however, the use of ionizing radiation and the potential need for exogenous contrast material adversely affect patient safety and work flow efficiency, respectively. Magnetic resonance (MR) imaging holds promise as an alternative for the evaluation of acute abdominopelvic pain. Critical causes of abdominopelvic pain may be detected with MR imaging without exogenous contrast material. MR imaging is sensitive for depicting tissue or fluid changes related to inflammation, a common process in causes of acute abdominopelvic pain. Fat suppression allows the detection of abnormal signal caused by inflamed tissue. MR imaging has proved sensitive in the detection of acute inflammatory diseases of the gallbladder and bile ducts, liver, pancreas, kidneys, collecting system, bowel, and pelvic soft tissues. Moreover, MR imaging without exogenous contrast material may be safely used in pregnant patients. Evolving roles for emergency department MR imaging include the assessment of vascular disease (including thromboembolic disease) and right upper quadrant pain. Emergency department MR imaging currently has limited availability, and its continued use will require further education regarding operation and image interpretation as well as further validation of cost-effectiveness. Nevertheless, current understanding of the diagnostic utility of this imaging method warrants continued study and the increased use of MR imaging in the evaluation of emergency department patients with acute abdominopelvic pain.


Pharmacological interventions for the prevention of bleeding in people undergoing definitive fixation or joint replacement for hip, pelvic and long bone fractures.
Pelvic, hip, and long bone fractures can result in significant bleeding at the time of injury, with further blood loss if they are treated with surgical fixation. People undergoing surgery are therefore at risk of requiring a blood transfusion and may be at risk of peri-operative anaemia. Pharmacological interventions for blood conservation may reduce the risk of requiring an allogeneic blood transfusion and associated complications. To assess the effectiveness of different pharmacological interventions for reducing blood loss in definitive surgical fixation of the hip, pelvic, and long bones. We used a predefined search strategy to search CENTRAL, MEDLINE, PubMed, Embase, CINAHL, Transfusion Evidence Library, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) from inception to 7 April 2022, without restrictions on language, year, or publication status. We handsearched reference lists of included trials to identify further relevant trials. We contacted authors of ongoing trials to acquire any unpublished data. We included randomised controlled trials (RCTs) of people who underwent trauma (non-elective) surgery for definitive fixation of hip, pelvic, and long bone (pelvis, tibia, femur, humerus, radius, ulna and clavicle) fractures only. There were no restrictions on gender, ethnicity, or age. We excluded planned (elective) procedures (e.g. scheduled total hip arthroplasty), and studies published since 2010 that had not been prospectively registered. Eligible interventions included: antifibrinolytics (tranexamic acid, aprotinin, epsilon-aminocaproic acid), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants, and non-fibrin sealants. Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE. We did not perform a network meta-analysis due to lack of data. We included 13 RCTs (929 participants), published between 2005 and 2021. Three trials did not report any of our predefined outcomes and so were not included in quantitative analyses (all were tranexamic acid versus placebo). We identified three comparisons of interest: intravenous tranexamic acid versus placebo; topical tranexamic acid versus placebo; and recombinant factor VIIa versus placebo. We rated the certainty of evidence as very low to low across all outcomes. Comparison 1. Intravenous tranexamic acid versus placebo Intravenous tranexamic acid compared to placebo may reduce the risk of requiring an allogeneic blood transfusion up to 30 days (RR 0.48, 95% CI 0.34 to 0.69; 6 RCTs, 457 participants; low-certainty evidence) and may result in little to no difference in all-cause mortality (Peto odds ratio (Peto OR) 0.38, 95% CI 0.05 to 2.77; 2 RCTs, 147 participants; low-certainty evidence). It may result in little to no difference in risk of participants experiencing myocardial infarction (risk difference (RD) 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 199 participants; low-certainty evidence), and cerebrovascular accident/stroke (RD 0.00, 95% CI -0.02 to 0.02; 3 RCTs, 324 participants; low-certainty evidence). We are uncertain if there is a difference between groups for risk of deep vein thrombosis (Peto OR 2.15, 95% CI 0.22 to 21.35; 4 RCTs, 329 participants, very low-certainty evidence), pulmonary embolism (Peto OR 1.08, 95% CI 0.07 to 17.66; 4 RCTs, 329 participants; very low-certainty evidence), and suspected serious drug reactions (RD 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 185 participants; very low-certainty evidence). No data were available for number of red blood cell units transfused, reoperation, or acute transfusion reaction. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures), and upgraded the evidence for transfusion requirement for a large effect. Comparison 2. Topical tranexamic acid versus placebo We are uncertain if there is a difference between topical tranexamic acid and placebo for risk of requiring an allogeneic blood transfusion (RR 0.31, 95% CI 0.08 to 1.22; 2 RCTs, 101 participants), all-cause mortality (RD 0.00, 95% CI -0.10 to 0.10; 1 RCT, 36 participants), risk of participants experiencing myocardial infarction (Peto OR 0.15, 95% CI 0.00 to 7.62; 1 RCT, 36 participants), cerebrovascular accident/stroke (RD 0.00, 95% CI -0.06 to 0.06; 1 RCT, 65 participants); and deep vein thrombosis (Peto OR 1.11, 95% CI 0.07 to 17.77; 2 RCTs, 101 participants). All outcomes reported were very low-certainty evidence. No data were available for number of red blood cell units transfused, reoperation, incidence of pulmonary embolism, acute transfusion reaction, or suspected serious drug reactions. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), inconsistency (moderate heterogeneity), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures, and high risk of attrition and reporting biases in one trial). Comparison 3. Recombinant factor VIIa versus placebo Only one RCT of 48 participants reported data for recombinant factor VIIa versus placebo, so we have not presented the results here. We cannot draw conclusions from the current evidence due to lack of data. Most published studies included in our analyses assessed the use of tranexamic acid (compared to placebo, or using different routes of administration). We identified 27 prospectively registered ongoing RCTs (total target recruitment of 4177 participants by end of 2023). The ongoing trials create six new comparisons: tranexamic acid (tablet + injection) versus placebo; intravenous tranexamic acid versus oral tranexamic acid; topical tranexamic acid versus oral tranexamic acid; different intravenous tranexamic acid dosing regimes; topical tranexamic acid versus topical fibrin glue; and fibrinogen (injection) versus placebo.


Grade I and II acromioclavicular dislocations: results of conservative treatment.
The purpose of this study was to assess the results of acute grade I and II acromioclavicular (AC) joint sprains treated by conservative measures. Between 1993 and 1997, 37 consecutive patients were treated conservatively for AC joint sprains, grade I and II in the Tossy classification. Of these patients, 4 were excluded (three lost to follow-up and one sustained a further AC injury), leaving a series of 33 patients. Among them, in 9 (27%), chronic AC joint pathology that required subsequent surgery developed at a mean of 26 months after injury. The remaining 24 were reviewed clinically and radiologically at a mean of 6.3 years (range, 4-8 years) after injury. At the latest follow-up, 17 of the 33 patients (52%) remained asymptomatic. Of the 24 patients reviewed, 7 complained of activity-related pain. Eight patients presented with residual anteroposterior instability. Tenderness at the AC joint as well as a positive cross-body test was observed in 12 patients. The mean Constant score at follow-up was 82 points. The x-ray films showed degenerative changes in 13 patients, ossification of the coracoclavicular ligaments in 2, an association of degenerative changes with ossification of the coracoclavicular ligaments in 3, and distal clavicular osteolysis in 3. Only 4 cases had no radiographic changes after this kind of AC injury. On the basis of these results, we conclude that the severity of the consequences after grade I and II AC sprains is underestimated.


Treatment with immunosuppressive therapy in patients with pars planitis: experience of a reference centre in Mexico.
To evaluate the clinical course of the patients with pars planitis that received immunosuppressive drugs. We retrospectively analysed the data of 10 years from 374 patients with pars planitis in a large reference centre in Mexico City and included 49 patients (92 eyes). Median age at presentation was 8 years. 35 patients (71.4%) were male and 43 patients (87.7%) had bilateral disease. Diverse immunosuppressive medications were used, mainly methotrexate (69.4%) and azathioprine (63.3%) with 18 patients requiring more than one drug. The main indications for starting immunosuppressive therapy were lack of response to initial treatment and advance disease at presentation. The results showed good response with steroid reduction (69.3% of patients), visual acuity improvement (51% of patients) and inflammatory disease reduction (59.1% of patients). In 25 patients (51%), steroids were started previous to immunosuppressors and in 24 (49%) at the same time without significant difference in clinical improvement (p=0.210) or visual outcome (p=0.498). Thirteen patients (26.5%) presented mild adverse effects. The median of the final visual acuity was 20/40. The median follow-up time was 44 months (range 13-115 months). Immunosuppressive therapy allows an adequate control of inflammatory disease in pars planitis, with clinical and visual improvement and steroid dose reduction.


Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228.
Histone deacetylases (HDACs) modulate chromatin structure by regulating acetylation of core histone proteins. HDAC inhibitors, such as depsipeptide FR901228 (FK228), induce growth arrest and apoptosis in a variety of human cancer cells by mechanisms that cannot be attributed solely to histone acetylation. This study evaluated the mechanisms by which FK228 mediates apoptosis in non-small-cell lung cancer (NSCLC) cells. Proliferation and apoptosis were assessed in a panel of NSCLC cell lines that vary in the expression of the growth-regulating proteins p53, pRb, and K-Ras treated with a clinically relevant dose of FK228 (25 ng/mL). Western blot and immunoprecipitation techniques were used to analyze expression of cell-cycle proteins (cyclin A, cyclin E, p53, and p21), signaling-related proteins (ErbB1, ErbB2, and Raf-1), activity of extracellular signal-regulated kinase 1 and 2 (ERK1/2), binding of mutant p53 and Raf-1 to heat shock protein (Hsp)90, and acetylation of Hsp90. FK228 treatment inhibited growth and induced apoptosis in NSCLC cells expressing wild-type or mutant p53. FK228 treatment led to altered expression of cyclin A, cyclin E, and p21, and to reduced expression of mutant, but not wild-type, p53. FK228-treated cells also were depleted of ErbB1, ErbB2, and Raf-1 proteins, and exhibited lower ERK1/2 activity. FK228 treatment also inhibited the binding of mutant p53 and Raf-1 to Hsp90; this inhibition was associated with acetylation of Hsp90. FK228 depletes the levels of several oncoproteins that are normally stabilized by binding to Hsp90 in cancer cells. The resulting ability of FK228 to diminish signal transduction via pathways involving Raf-1 and ERK may contribute to the potency and specificity of this novel antitumor agent.


Hematopoietic stem-cell contribution to ectopic skeletogenesis.
Fibrodysplasia ossificans progressiva is a rare genetic disorder of ectopic skeletogenesis associated with dysregulation of bone morphogenetic protein (BMP) signaling. Hematopoietic cells have been implicated in the ectopic skeletogenesis of fibrodysplasia ossificans progressiva, and their replacement has been postulated as a possible cure. However, the definitive contribution of hematopoietic cells to the pathogenesis of ectopic skeletogenesis remains obscure. We employed both careful clinical observation and in vivo murine transplantation studies to more precisely determine the contribution of hematopoietic cells to ectopic skeletogenesis. We identified a patient with fibrodysplasia ossificans progressiva who had undergone bone marrow transplantation for the treatment of intercurrent aplastic anemia twenty-five years earlier and investigated whether the clinical course of the fibrodysplasia ossificans progressiva had been influenced by bone marrow replacement or immunosuppression, or both. In complementary studies, we transplanted hematopoietic stem cells from constitutively expressing LacZ transgenic mice to identify the contribution of hematopoietic cells to BMP4-induced heterotopic ossification, a histopathologic model of fibrodysplasia ossificans progressiva. We found that replacement of hematopoietic cells was not sufficient to prevent ectopic skeletogenesis in the patient with fibrodysplasia ossificans progressiva but pharmacologic suppression of the apparently normal donor immune system following transplantation in the new host modulated the activity of the fibrodysplasia ossificans progressiva and diminished the expression of skeletal ectopia. In complementary murine transplantation studies, we found that cells of hematopoietic origin contributed to the early inflammatory and late marrow-repopulating stages of BMP4-induced heterotopic ossification but were not represented in the fibroproliferative, chondrogenic, or osteogenic stages of heterotopic ossification. Interestingly, both recombinant human BMP4 induction in an animal model and the dysregulated BMP signaling pathway in a patient with fibrodysplasia ossificans progressiva were sufficient to recruit at least two populations of cells, one of hematopoietic origin and at least one of non-hematopoietic origin, that contribute to the formation of an ectopic skeleton. Taken together, these findings demonstrate that bone marrow transplantation did not cure fibrodysplasia ossificans progressiva in the patient in this study, most likely because the hematopoietic cell population is not the site, or at least not the dominant site, of the intrinsic dysregulation of the BMP signaling pathway in fibrodysplasia ossificans progressiva. However, following transplantation of bone marrow from a presumably normal donor, immunosuppression of the immune system appeared to ameliorate activation of ectopic skeletogenesis in a genetically susceptible host. Thus, cells of hematopoietic origin may contribute to the formation of an ectopic skeleton, although they are not sufficient to initiate the process alone.


Age-related changes in bone mineral content and density in intact male F344 rats.
This study was undertaken to determine whether age-related bone loss occurs in intact male F344 rats. Bone loss was assessed in male F344 rats aged 3 to 27 months by scanning different bones using peripheral quantitative computed tomography (pQCT) densitometry. Cancellous and cortical bones were analyzed at the vertebra, proximal tibial metaphysis (PTM), and the neck of the femur. Cortical bone was also analyzed at the tibial and femoral diaphysis and at the tibio-fibula junction. In the vertebra, cancellous bone mineral content (Cn. BMC) did not change significantly with age. Cancellous bone mineral density (Cn. BMD) gradually decreased from 9 months onwards; and at 27 months of age, there was a 29% (p < 0.0001) decrease, when compared with 9-month-old animals. No significant change was observed in cortical bone mineral content (Ct. BMC) and cortical bone mineral density (Ct. BMD) with age. In the PTM, bone loss started to occur after 18 months of age. At 27 months of age, Cn. BMC decreased by 58% (p < 0.0001) and Cn. BMD also decreased by 58% (p < 0.0001). Ct. BMC decreased by 28% (p < 0.0001) in 27-month-old animals, whereas Ct. BMD was not affected by aging. At the tibio-fibula junction, Ct. BMC and Ct. BMD decreased after 18 months of age. At 27 months, Ct. BMC and Ct. BMD had decreased by 8% (p < 0.001) and 3% (p < 0.0001), respectively. Ct. BMC in the tibial diaphysis did not change significantly with age, whereas Ct. BMD decreased by 1% (p < 0.05) at 27 months. In the neck of the femur, Cn. BMC increased up to 24 months of age. Cn. BMD increased up to 18 months of age and decreased by 9% (p < 0.05) at 24 months and 11% (p < 0.001) at 27 months of age when compared with 18-month-old animals. Ct. BMC and Ct. BMD increased with age. In conclusion, although some components of the PTM decreased appreciably with age, in this study, most of the bone parameters analyzed either increased or did not change significantly with age. We conclude that unlike male Sprague Dawley rats, male F344 rats appear not to be a good model for studying age-related bone loss as occurs in aging men.


Gibbs free energy of formation of chlordecone and potential degradation products: implications for remediation strategies and environmental fate.
Chlordecone (C(10)Cl(10)O; CAS number 143-50-0) has been used extensively as an organochlorine insecticide but is nowadays banned under The Stockholm Convention on Persistent Organic Pollutants (POPs). A search for chlordecone-respiring organisms and choosing between reductive versus oxidative remediation tools and strategies to clean up chlordecone-polluted environments would benefit from the availability of Gibbs free energy data of chlordecone and its potential dechlorination products. Presently such data are not available. Polycyclic "cage" molecules of which chlordecone is an example contain considerable strain energy. It is not a priori clear how this affects the thermodynamic properties of the chlorinated members of this unique class of compounds and to what extent redox potentials for the halogenated congeners are different from those of other aliphatic and aromatic organohalogens. We performed ab initio quantum chemical calculations to estimate Δ(f)H(m)° and Δ(f)G(m)° values of chlordecone and selected dechlorination products and used these data to calculate their Gibbs free energy and redox potential. With redox potentials in the range of 336-413 mV chlordecone has an E(o)' value similar to that of other organochlorines. The results indicate that there are no thermodynamic reasons why chlordecone-respiring or -fermenting organisms should not exist.


Cardiovascular physiology and pathophysiology in Down syndrome.
Down syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Individuals with Ds demonstrate cognitive deficits in addition to comorbidities including cardiac defects, pulmonary arterial hypertension (PAH), low blood pressure (BP), and differences in autonomic regulation. Many individuals with Ds are born with heart malformations and some can be surgically corrected. Lower BP at rest and in response to exercise and other stressors are a prevalent feature in Ds. These reduced cardiovascular responses may be due to underlying autonomic dysfunction and have been implicated in lower exercise/work capacity in Ds, which is an important correlate of morbidity, mortality and quality of life. Exercise therapy can be beneficial to normalize autonomic function and may help prevent the development of co-morbidities in Ds. We will review cardiovascular physiology and pathophysiology in individuals with Ds, along with exercise therapy and special considerations for these individuals.


ProMAT: protein microarray analysis tool.
ProMAT is a software tool for statistically analyzing data from enzyme-linked immunosorbent assay microarray experiments. The software estimates standard curves, sample protein concentrations and their uncertainties for multiple assays. ProMAT generates a set of comprehensive figures for assessing results and diagnosing process quality. The tool is available for Windows or Mac, and is distributed as open-source Java and R code. ProMAT is available at http://www.pnl.gov/statistics/ProMAT. ProMAT requires Java version 1.5.0 and R version 1.9.1 (or more recent versions). ProMAT requires either Windows XP or Mac OS 10.4 or newer versions.


Will you survive the services revolution?
Of late, offshoring and outsourcing have become political hot buttons. These o words have been conflated to mean that high-paying, white-collar jobs have been handed to well-trained but less expensive workers in India and other locales. The brouhaha over the loss of service jobs, which currently account for over 80% of private-sector employment in the United States, is not merely an American phenomenon. The fact is that service-sector jobs in all developed countries are at risk. Regardless of what the politicians now say, worry focused on offshoring and outsourcing misses the point, the author argues. We are in the middle of a fundamental change, which is that services are being industrialized. Three factors in particular are combining with outsourcing and offshoring to drive that transformation: The first is increasing global competition, where just as with manufactured goods in the recent past, foreign companies are offering more services in the United States, taking market share from U.S. companies. The second is automation: New hardware and software systems that take care of back-room and front-office tasks such as counter operations, security, billing, and order taking are allowing firms to dispense with clerical, accounting, and other staff positions. The third is self-service. Why use a travel agent when you can book your own flight, hotel, and rental car online? As these forces combine to sweep across the service sector, executives of all stripes must start thinking about arming and defending themselves, just as their manufacturing cousins did a generation ago. This will demand proactive and far-reaching changes, including focusing specifically on customer preference, quality, and technological interfaces; rewiring strategy to find new value from existing and unfamiliar sources; de-integrating and radically reassembling operational processes; and restructuring the organization to accommodate new kinds of work and skills.


Mobility limitation in the older patient: a clinical review.
Mobility limitations are common in older adults, affecting the physical, psychological, and social aspects of an older adult's life. To identify mobility risk factors, screening tools, medical management, need for physical therapy, and efficacy of exercise interventions for older primary care patients with limited mobility. Search of PubMed and PEDro from January 1985 to March 31, 2013, using the search terms mobility limitation, walking difficulty, and ambulatory difficulty to identify English-language, peer-reviewed systematic reviews, meta-analyses, and Cochrane reviews assessing mobility limitation and interventions in community-dwelling older adults. Articles not appearing in the search referenced by reviewed articles were also evaluated. The most common risk factors for mobility impairment are older age, low physical activity, obesity, strength or balance impairment, and chronic diseases such as diabetes or arthritis. Several tools are available to assess mobility in the ambulatory setting. Referral to physical therapy is appropriate, because physical therapists can assess mobility limitations and devise curative or function-enhancing interventions. Relatively few studies support therapeutic exercise to improve mobility limitation. Strong evidence supports resistance and balance exercises for improving mobility-limiting physical weakness and balance disorders. Assessing a patient's physical environment and the patient's ability to adapt to it using mobility devices is critical. Identification of older adults at risk for mobility limitation can be accomplished through routine screening in the ambulatory setting. Addressing functional deficits and environmental barriers with exercise and mobility devices can lead to improved function, safety, and quality of life for patients with mobility limitations.


Drosophila sechellia: A Genetic Model for Behavioral Evolution and Neuroecology.
Defining the mechanisms by which animals adapt to their ecological niche is an important problem bridging evolution, genetics, and neurobiology. We review the establishment of a powerful genetic model for comparative behavioral analysis and neuroecology, Drosophila sechellia. This island-endemic fly species is closely related to several cosmopolitan generalists, including Drosophila melanogaster, but has evolved extreme specialism, feeding and reproducing exclusively on the noni fruit of the tropical shrub Morinda citrifolia. We first describe the development and use of genetic approaches to facilitate genotype/phenotype associations in these drosophilids. Next, we survey the behavioral, physiological, and morphological adaptations of D. sechellia throughout its life cycle and outline our current understanding of the genetic and cellular basis of these traits. Finally, we discuss the principles this knowledge begins to establish in the context of host specialization, speciation, and the neurobiology of behavioral evolution and consider open questions and challenges in the field.


Non-invasive preimplantation genetic testing (niPGT): the next revolution in reproductive genetics?
Preimplantation genetic testing (PGT) encompasses methods that allow embryos to be tested for severe inherited conditions or for chromosome abnormalities, relevant to embryo health and viability. In order to obtain embryonic genetic material for analysis, a biopsy is required, involving the removal of one or more cells. This invasive procedure greatly increases the costs of PGT and there have been concerns that embryo viability could be compromised in some cases. The recent discovery of DNA within the blastocoele fluid (BF) of blastocysts and in spent embryo culture media (SCM) has led to interest in the development of non-invasive methods of PGT (niPGT). This review evaluates the current scientific evidence regarding non-invasive genetic assessment of preimplantation embryos. The success of different PGT methodologies in collecting and analysing extra-embryonic DNA is evaluated, and consideration is given to the potential biological and technical hindrances to obtaining a reliable clinical diagnosis. Original research and review papers concerning niPGT were sourced by searching PubMed and Google Scholar databases until July 2019. Searches comprised the keywords: 'non-invasive'; 'cell-free DNA'; 'blastocentesis'; 'blastocoel fluid'; 'spent culture media'; 'embryo culture medium'; 'preimplantation genetic testing'; 'preimplantation genetic diagnosis'; 'preimplantation genetic screening'; and 'aneuploidy'. Embryonic DNA is frequently detectable in BF and SCM of embryos produced during IVF treatment. Initial studies have achieved some success when performing cytogenetic and molecular genetic analysis. However, in many cases, the efficiency has been restricted by technical complications associated with the low quantity and quality of the DNA. Reported levels of ploidy agreement between SCM/BF samples and biopsied embryonic cells vary widely. In some cases, a discrepancy with respect to cytogenetic data obtained after trophectoderm biopsy may be attributable to embryonic mosaicism or DNA contamination (usually of maternal origin). Some research indicates that aneuploid cells are preferentially eliminated from the embryo, suggesting that their DNA might be over-represented in SCM and BF samples; this hypothesis requires further investigation. Available data suggest that BF and SCM samples frequently provide DNA templates suitable for genetic analyses, offering a potential means of PGT that is less expensive than traditional methods, requires less micromanipulation skill and poses a lower risk to embryos. Critically, DNA isolation and amplification protocols must be optimised to reproducibly obtain an accurate clinical diagnosis, whilst minimising the impact of confounding factors such as contamination. Further investigations are required to understand the mechanisms underlying the release of embryonic DNA and to determine the extent to which this material reflects the true genetic status of the corresponding embryo. Currently, the clinic al potential of niPGT remains unknown.


Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide.
Inhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma. Bronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual-specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis. Compared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide-treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects. Expression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy.


Improved detection limits of protein optical fiber biosensors coated with gold nanoparticles.
The study presented herein investigates a novel arrangement of fiber-optic biosensors based on a tilted fiber Bragg grating (TFBG) coated with noble metal nanoparticles, either gold nanocages (AuNC) or gold nanospheres (AuNS). The biosensors constructed for this study demonstrated increased specificity and lowered detection limits for the target protein than a reference sensor without gold nanoparticles. The sensing film was fabricated by a series of thin-film and monolayer depositions to attach the gold nanoparticles to the surface of the TFBG using only covalent bonds. Though the gold nanoparticle integration had not yet been optimized for the most efficient coverage with minimum number of nanoparticles, binding AuNS and AuNC to the TFBG biosensor decreased the minimum detected target concentrations from 90 nM for the reference sensor, to 11 pM and 8 pM respectively. This improvement of minimum detection is the result of a reduced non-specific absorption onto the gold nanoparticles (by functionalization of the external surface of the gold nanoparticles), and of an optical field enhancement due to coupling between the photonic modes of the optical fiber and the localized surface plasmon resonances (LSPR) of the gold nanoparticles. This coupling also increased the sensitivity of the TFBG biosensor to changes in its local environment. The dissociation constant (Kd) of the target protein was also characterized with our sensing platform and found to be in good agreement with that of previous studies.


The influence of foot posture on the cost of transport in humans.
Although humans appear to be specialized for endurance running, the plantigrade posture of our feet, in which the heel contacts the substrate at the beginning of a step, seems incompatible with economical running. In this study, we tested the hypothesis that plantigrade foot posture reduces the energetic cost of transport (COT) during walking in humans. When human subjects walked with their heels slightly elevated in a 'low-digitigrade' posture, COT increased by 53% above that of normal plantigrade walking. By contrast, there was no difference in COT when subjects ran with digitigrade versus plantigrade foot posture. Stride frequency increased and stride length decreased when subjects switched to digitigrade walking; however, this change did not influence the COT. Additionally, we found that possible reductions in postural stability appear not to have caused the elevated cost of digitigrade walking. Digitigrade walking, however, did (1) increase the external mechanical work performed by the limbs; (2) reduce the pendular exchange of kinetic and potential energy of the center of mass; (3) increase the average ground reaction force moment at the ankle joint; and (4) increase the recruitment of major extensor muscles of the ankle, knee, hip and back. These observations suggest that plantigrade foot posture improves the economy of walking. Relative to other mammals, humans are economical walkers, but not economical runners. Given the great distances hunter-gatherers travel, it is not surprising that humans retained a foot posture, inherited from our more arboreal great ape ancestors, that facilitates economical walking.


Qualitative and quantitative analysis of precipitate formation following interaction of chlorhexidine with sodium hypochlorite, neem, and tulsi.
The interaction between chlorhexidine (CHX) and sodium hypochlorite (NaOCl) yields a thick precipitate capable of occluding dentinal tubules. Previous studies are unclear as to the above-mentioned precipitate contains para-chloroaniline (PCA) or not. PCA is a known toxic and carcinogenic compound which may lead to methemoglobinemia in humans. This study aims to evaluate the precipitate formed on combination of different irrigants, weigh the amount of precipitate formed and to analyze the precipitate for PCA by using thin layer chromatography (TLC), high performance liquid chromatography (HPLC), column chromatography (CC), electron spray ionization mass spectrometry (ESI-MS), Ultraviolet (UV), and nuclear magnetic resonance (1H-NMR and C-13 NMR). Four different irrigants namely 2% CHX gluconate, 3% NaOCl, 5% neem and 5% tulsi were taken in different test tubes. Group 1, 2 and 3 included 1 ml 2% CHX combined with 1 ml each of 3% NaOCl, 5% neem and 5% tulsi. Group 4 and 5 comprised of 1 ml 3% NaOCl in combination with 1 ml 5% each of neem and tulsi. Finally, group 6 constituted 1 ml 5% neem mixed with 1 ml 5% tulsi. Each group was observed for 2 min for the formation of any precipitate, and the formed precipitate was weighed and analyzed using 1H-NMR and C-13 NMR, TLC, CC, HPLC, ESI-MS, and UV. One-way ANOVA and Post hoc-Tukey test were used. Presence of PCA was detected in group 1 (CHX + NaOCl), group 2 (CHX + neem) and group 3 (CHX + tusli) in all the sensitive methods employed. The presence of PCA in precipitate was confirmed by TLC, CC, HPLC, ESI-MS, and UV. Based on the results of the present study, we assume that components in CHX are responsible for precipitate formation which contains PCA as well. Extrusion of precipitate beyond the apex may cause periapical tissue damage and delay wound healing at the same time.


[Therapy with high-flow nasal prongs in preterm infants].
Despite of improved survival of premature infants, the incidence of long-term pulmonary complications, mostly associated with ventilation-induced lung injury, remains high. Non invasive ventilation (NIV) is able to reduce the adverse effects of mechanical ventilation. Although nasal continuous positive airway pressure (NCPAP) is an effective mode of NIV, traumatic nasal complications and intolerance of the nasal interface are common. Recently high flow nasal cannula (HFNC) is emerging as an efficient, better tolerated form of NIV, allowing better access to the baby's face, which may improve nursing, feeding and bonding. The aim of this review is to discuss the available evidence of effectiveness and safety of HFNC in preterm newborns with respiratory distress syndrome (RDS). It is known that distending pressure generated by HFNC increases with increasing flow rate and decreasing infant size and varies according to the amount of leaks by nose and mouth. The effects of HFNC on lung mechanics, its clinical efficacy and safety are still insufficiently investigated. In conclusion, there is a growing evidence of the feasibility of HFNC as an alternative mode of NIV. However, further larger randomized trials are required, before being able to recommend HFNC in the treatment of moderate respiratory distress of preterm infants.


An exploration of faculty perspectives on the in-training evaluation of residents.
The in-training evaluation report (ITER) is the most widely used approach to the evaluation of residents' clinical performance. Participants' attitudes toward the process may influence how they approach the task of resident evaluation. Whereas residents find ITERs most valuable when they perceive their supervisors to be engaged in the process, faculty attitudes have not yet been explored. The authors studied faculty supervisors' experiences and perceptions of the ITER process to gain insight into the factors that influence faculty engagement. Using a grounded theory approach, semistructured interviews were completed in 2008 with a purposive sample of 17 faculty involved in resident evaluation at one Canadian medical school. Constant comparative analysis for emergent themes was conducted. Three major themes emerged: (1) Faculty engagement was apparent, with a widely held view that ITERs were a worthwhile endeavor. (2) Fragmentation of the evaluation system compromised evaluators' ability to produce meaningful ITERs. Fragmentation appeared to be a system problem, elements of which included time constraints, inconsistency in approach to ITE, and lack of continuity between educational assignments. (3) Faculty found the challenge of giving negative feedback daunting and struggled to avoid harming residents. Faculty engagement in the ITER process may be compromised by both system and interpersonal challenges. These challenges may render ITERs less meaningful than faculty intend. Training programs must complement ITE with other tools to achieve robust systems of evaluation.


Reduced mortality associated with breast-feeding-acquired HIV infection and breast-feeding among HIV-infected children in Zambia.
In developing countries, where mother-to-child transmission of HIV through breast-feeding is common, little is known about the impact of postpartum transmission on child survival. This study assessed whether children infected postpartum have longer survival from time of infection versus those infected during gestation or delivery. We used a prospective cohort study to analyze data from 213 HIV-infected children enrolled in a breast-feeding intervention trial in Lusaka, Zambia (2001 to 2004). We compared mortality 1 year after HIV infection in children stratified by age of infection: 0 to 3 days (intrauterine [IU] group), 4 to 40 days (intrapartum/early postpartum [IP/EPP] group), and >40 days (postpartum [PP] group). A total of 61, 71, and 81 children were infected in the IU, IP/EPP, and PP groups, respectively. Children with intrauterine or intrapartum/early postpartum transmission had higher mortality over the first 12 months after infection than children with postpartum transmission (P = 0.001 and P = 0.006, respectively); no differences were detected between children with intrauterine and intrapartum/early postpartum transmission. Nearly 20% of the IU and IP/EPP groups died by 100 days after infection, whereas nearly 10% of the PP group had died by this time. After adjusting for birth weight, maternal CD4 cell count, breast-feeding, and maternal death, children infected postpartum had one quarter the mortality rate (hazard ratio [HR] = 0.27, 95% confidence interval [CI]: 0.15 to 0.50) of those infected in utero. Stopping breast-feeding increased mortality in infected children (HR = 3.1, 95% CI: 1.8 to 5.3). This study demonstrates a survival benefit among children infected postpartum versus children infected during pregnancy or delivery and a benefit to increased breast-feeding duration among infected children. Testing children for HIV early may provide a means to allow for earlier intervention.


Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults.
Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke. In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (≥5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations). Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only. Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.


Over-expression of the bacterial phytase US417 in Arabidopsis reduces the concentration of phytic acid and reveals its involvement in the regulation of sulfate and phosphate homeostasis and signaling.
Phytic acid (PA) is the main phosphorus storage form in plant seeds. It is recognized as an anti-nutrient for humans and non-ruminant animals, as well as one of the major sources of phosphorus that contributes to eutrophication. Therefore, engineering plants with low PA content without affecting plant growth capacity has become a major focus in plant breeding. Nevertheless, lack of knowledge on the role of PA seed reserves in regulating plant growth and in maintaining ion homeostasis hinders such an agronomical application. In this context, we report here that the over-expression of the bacterial phytase PHY-US417 in Arabidopsis leads to a significant decrease in seed PA, without any effect on the seed germination potential. Interestingly, this over-expression also induced a higher remobilization of free iron during germination. Moreover, the PHY-over-expressor lines show an increase in inorganic phosphate and sulfate contents, and a higher biomass production after phosphate starvation. Finally, phosphate sensing was altered because of the changes in the expression of genes induced by phosphate starvation or involved in phosphate or sulfate transport. Together, these results show that the over-expression of PHY-US417 reduces PA concentration, and provide the first evidence for the involvement of PA in the regulation of sulfate and phosphate homeostasis and signaling.